Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system

Abstract

Differentiating oligodendrocytes generate myelin to ensure rapid saltatory conduction in the vertebrate central nervous system. Although oligodendroglial differentiation and myelination are accompanied by dramatic chromatin reorganizations, previously studied chromatin remodelers had only limited direct effects on the process. To study the functional significance of chromatin changes for myelination and identify relevant remodelers, we deleted Ep400, the central ATP-hydrolyzing subunit of the TIP60/EP400 complex, at defined times of mouse oligodendrocyte development. Whereas Ep400-deficient oligodendrocyte precursors develop normally, terminal differentiation and myelination are dramatically impaired. Mechanistically, Ep400 interacts with transcription factor Sox10, binds to regulatory regions of the Myrf gene and is required to induce this central transcriptional regulator of the myelination program. In addition to reduced and aberrant myelin formation, oligodendrocytes exhibit increased DNA damage and apoptosis so that numbers never reach wildtype levels during the short lifespan of Ep400-deficient mice. Ep400 deletion in already mature oligodendrocytes remains phenotypically inapparent arguing that Ep400 is dispensable for myelin maintenance. Given its essential function in myelin formation, modulation of Ep400 activity may be beneficial in conditions such as multiple sclerosis where this process is compromised.

Crazy Little Thing Called Sox—New Insights in Oligodendroglial Sox Protein Function

“…During myelination, chromatin is heavily reorganized to allow transcription of myelin genes. The TIP60/EP400 complex, a chromatin remodeling complex of the INO80/SWR subfamily, was recently identified to interact with Sox10 during oligodendroglial development [48]. Deletion of Ep400, which is the ATP-hydrolyzing subunit of this chromatin remodeling complex, in Nestin-positive NSCsshowed that it is dispensable for OPC specification, proliferation, and migration in the murine embryonic spinal cord.…”

Oligodendroglial Epigenetics, from Lineage Specification to Activity-Dependent Myelination

“…Ablating DNMT1- or DNMT3A-mediated DNA methylation or EED-mediated histone methylation in OPCs does not result in ectopic proliferation in vitro or in vivo, and even slightly negatively perturbates OPC proliferation during development [ 87 , 92 , 133 ]. Inversely, TET1-mediated DNA hydroxymethylation does not seem to affect neonatal or adult OPC proliferation in vitro or in vivo [ 89 , 134 ].…”

“…Indeed, the ablation of DNA methyltransferases in developmental and adult post-mitotic OPCs has a slight effect on myelination and remyelination [ 87 , 133 ]. Recent studies also highlight an age-dependent role of demethylation on OPC differentiation, suggesting a more important role of DNA hydroxymethylation in adult oligodendroglial cells [ 89 , 134 ]. In particular, TET1-mediated DNA hydroxymethylation targets genes involved in the late stages of OPC differentiation, such as biosynthesis and neuroglial communication [ 89 , 119 , 134 ].…”

“…Recent studies also highlight an age-dependent role of demethylation on OPC differentiation, suggesting a more important role of DNA hydroxymethylation in adult oligodendroglial cells [ 89 , 134 ]. In particular, TET1-mediated DNA hydroxymethylation targets genes involved in the late stages of OPC differentiation, such as biosynthesis and neuroglial communication [ 89 , 119 , 134 ]. The ablation of Tet1 in adult OPCs is sufficient to reduce DNA hydroxymethylation at these specific genomic sites, downregulating their expression and blocking OL late differentiation [ 134 ].…”

Novel functional proteins coded by the human genome discovered in metastases of melanoma patients

“…The EP400P1 protein is a homologue of the E1Abinding chromatin remodeller EP400, albeit containing only the EP400_N domain with unknown function (Elsesser et al 2019) and lacking a catalytic DEAD nuclease domain. Such an arrangement may indicate a regulatory function that is related to the longer homologue, EP400.…”